A phase II evaluation of cisplatin, bleomycin, and mitomycin-C in patients with recurrent squamous cell carcinoma of the cervix.

Cisplatin, bleomycin, and mitomycin-C were used to treat 25 patients with recurrent squamous cell carcinoma of the cervix. Six patients had a partial response, yielding a total response rate of 27%. Nine patients had stable disease. The median survival for the whole group was 30 weeks. The median survival for responders was 32 weeks. The median progression free interval for the whole group was 12 weeks and the median progression-free free interval for responders was 14 weeks. The toxicities noted were primarily nausea, vomiting, and myelosuppression. The combination of cisplatin, bleomycin, and mitomycin-C has modest effectiveness in the treatment of recurrent squamous cell carcinoma of the cervix, but represents no improvement over single-agent chemotherapy.     

Prospective treatment of advanced or recurrent endometrial carcinoma with cisplatin, doxorubicin, and cyclophosphamide

Both single-agent cisplatin and the combination of doxorubicin and cyclophosphamide demonstrated moderate activity against endometrial carcinoma in earlier salvage trials. Since January 1979, 102 patients with advanced primary (n = 42) or recurrent (n = 60) endometrial carcinoma were prospectively treated with cisplatin (50 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) (PAC). PAC was administered monthly until disease progression or toxicity precluded additional therapy. Patients received a median of five treatment cycles (range 1-13). Of the 87 patients with measurable disease, 12 had a complete clinical response, while 27 had a partial clinical response, for an overall objective response rate of 45%. No differences in response rates between primary and recurrent disease patients were noted. Median time to response was 2.5 months with a median response duration of 4.8 months. Nonresponders included 33 patients with stable disease and 15 with progression. Median progression-free survival for all patients was 6 months. Dose escalation was possible in 25% of patients; however, 52% of patients required dose reductions during treatment. Clinically significant toxicities included neutropenia (65%), anemia (47%), emesis (21%), nephrotoxicity (17%), and neurotoxicity (4%). Our study indicates that endometrial cancer is significantly responsive to PAC. Enthusiasm for this regimen should be tempered by the limited duration of response and substantial treatment toxicity.     

Melphalan, 5-fluorouracil, and medroxyprogesterone acetate in metastatic endometrial carcinoma

Fifty consecutive patients with recurrent and metastatic endometrial carcinoma were treated with melphalan, 5-fluorouracil, and medroxyprogesterone acetate with or without tamoxifen as first-line chemotherapy. The objective response rate was 48%, with 20% complete responses. The estimated median progression-free survival time was only five months (0.5 to 65 months) with estimated two- and five-year progression-free survival rates of 16 and 13%, respectively. The estimated median progression-free survival time was 24 months for complete responders; the progression-free survival times were significantly longer than the survival times (median = four months) for all other patients (P = .0002). Whether or not the addition of cytotoxic chemotherapy to progesterone hormonal therapy for metastatic endometrial carcinoma lengthens survival time is still open to question.     

Treatment of metastatic stromal tumors of the ovary with cisplatin, doxorubicin, and cyclophosphamide

From September 1981 until June 1986, eight patients with metastatic ovarian stromal tumors were entered into a prospective phase II study to determine the efficacy of a chemotherapy regimen combining cisplatin, doxorubicin, and cyclophosphamide. Patients received cisplatin 40-50 mg/m2 intravenously (IV), doxorubicin 40-50 mg/m2 IV, and cyclophosphamide 400-500 mg/m2 IV, all on day 1 every 28 days. The median age was 43 years (range 24-65 years). Two patients had stage II disease, one had stage III, and five had recurrent disease (original stage: four stage I and one stage III). The median number of chemotherapy cycles was six (range four to 14). Three patients (38%) had a complete response to therapy (two confirmed by second-look laparotomy), and two patients (25%) achieved a partial response (one verified by second-look laparotomy). The overall response rate was 63%. Toxicity was minimal. Four patients are disease-free at 13+ to 48+ months, one patient is alive with disease at six+ months, and three patients are dead of tumor at four, 17, and 36 months from the start of chemotherapy. These results indicate that the combination of cisplatin, doxorubicin, and cyclophosphamide has modest activity in the treatment of metastatic ovarian stromal tumor.     

Prospective treatment of advanced or recurrent endometrial carcinoma with cisplatin, doxorubicin, and cyclophosphamide

Both single-agent cisplatin and the combination of doxorubicin and cyclophosphamide demonstrated moderate activity against endometrial carcinoma in earlier salvage trials. Since January 1979, 102 patients with advanced primary (n = 42) or recurrent (n = 60) endometrial carcinoma were prospectively treated with cisplatin (50 mg/m²), doxorubicin (50 mg/m²), and cyclophos-phamide (500 mg/m²) (PAC). PAC was administered monthly until disease progression or toxicity precluded additional therapy. Patients received a median of five treatment cycles (range 1–13). Of the 87 patients with measurable disease, 12 had a complete clinical response, while 27 had a partial clinical response, for an overall objective response rate of 45%. No differences in response rates between primary and recurrent disease patients were noted. Median time to response was 2.5 months with a median response duration of 4.8 months. Nonresponders included 33 patients with stable disease and 15 with progression. Median progression-free survival for all patients was 6 months. Dose escalation was possible in 25% of patients; however, 52% of patients required dose reductions during treatment. Clinically significant toxicities included neutropenia (65%), anemia (47%), emesis (21%), nephrotoxicity (17%), and neurotoxicity (4%). Our study indicates that endometrial cancer is significantly responsive to PAC. Enthusiasm for this regimen should be tempered by the limited duration of response and substantial treatment toxicity.     

Treatment of fallopian tube carcinoma with cisplatin, doxorubicin, and cyclophosphamide

Primary carcinoma of the fallopian tube is uncommon and is often treated using regimens active in ovarian carcinoma. Evidence is scant that such therapies benefit patients with fallopian tube carcinoma. Between December 1979 and July 1988, we treated 18 patients who had adenocarcinoma of the fallopian tube with the combination of cisplatin (50 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) administered intravenously on 1 day every 28 days. Histologic confirmation of fallopian tube carcinoma was obtained before entry in the study. Three patients had stage I disease, five had stage II, nine had stage III, and one had stage IV. Sixteen patients received the combination therapy as first-line treatment after cytoreductive surgery, and two patients received it for recurrent carcinoma. Seven patients had clinically measurable disease at the start of therapy. Two of these patients had a complete clinical response, two had stable disease, and three had progressive disease. Eight of the 15 patients with stages II-IV disease underwent second-look laparotomy; four had a complete response to therapy and four had a partial response, making the overall response rate 53%. The toxicity of the regimen was moderate. The median survival was 81 months. Patients with stages II-IV disease had a median survival of 43.9 months and a progression-free survival of 22.5 months. This regimen appears to be active in fallopian tube carcinoma and can result in response rates comparable to those reported for epithelial ovarian cancer.     

Chemotherapy plus Sequential Hormonal Therapy for Advanced and Recurrent Endometrial Carcinoma: A Phase II Study

We evaluated the therapeutic value of sequential cyclical hormonal therapy (megestrol acetate, and tamoxifen citrate) plus single-agent chemotherapy (carboplatin) in the outpatient management of advanced or recurrent endometrial cancer. Carboplatin (300 mg/m²) was administered every 4 weeks for six courses or until disease progression. In addition, patients alternated megestrol acetate (80 mg orally twice daily) with tamoxifen citrate (20 mg orally twice daily) every 3 weeks. Thirteen of 18 (72.2%) patients were considered evaluable. Four patients (30.8%) had a complete response, six (46.2%) had a partial response, one (7.7%) had stable disease, and two patients (15.4%) progressed. Six of seven patients with vaginal disease responded. The median progression-free interval was 14 months for complete responders. Two patients (15.4%) are alive with no evidence of disease at 41 and 59 months. Seven of 13 patients experienced a hematologic toxicity (six grade 2, one grade 3); all resolved within 2 weeks. Dose reduction of carboplatin to 200 mg/m²was required in one patient. No other toxicities were encountered. The median survival for all patients is 11 months, and is 33 months for complete responders. We conclude that a regimen of carboplatin plus sequential hormonal therapy shows promise in this pilot study for the treatment of advanced or recurrent endometrial cancer.     

Systemic therapy for advanced uterine sarcoma: a systematic review of the literature

OBJECTIVE: To conduct a systematic review of the literature regarding the systemic treatment of advanced uterine sarcoma and provide an evidence-based summary of the available literature. METHODS: MEDLINE, EMBASE, and the Cochrane Library databases were searched. "Uterine sarcoma," "leiomyosarcoma," "mixed mesodermal tumor," "chemotherapy," and "systemic therapy" were combined with the search terms for study designs. RESULTS: Three randomized controlled trials and 24 prospective phase II trials were included in the systematic review. In a randomized trial of doxorubicin versus doxorubicin plus cyclophosphamide for advanced or recurrent uterine sarcoma, doxorubicin produced an overall response rate (RR) of 19% and median survival of 11.6 months, which was similar to the response with combination chemotherapy (RR 19%, median survival 10.9 months). A randomized trial comparing ifosfamide plus cisplatin versus ifosfamide alone in mixed mesodermal tumors showed a significant improvement in RR and progression-free survival with the combination compared with ifosfamide alone, however, the combination was associated with increased toxicity including death. A randomized trial comparing doxorubicin to doxorubicin with dacarbazine in women with advanced or recurrent uterine sarcoma demonstrated a significantly higher RR with the combination (P < 0.05), but no significant difference in survival. CONCLUSIONS: Offering palliative chemotherapy to patients with advanced, unresectable uterine sarcoma who are symptomatic from this disease is a reasonable decision. Doxorubicin is an option for women with advanced uterine sarcoma. The combination of cisplatinum and ifosfamide is also an option for women with metastatic mixed mesodermal tumors; however, this combination is associated with significant toxicity when compared to ifosfamide alone.     

Intravenous Cisplatin, Doxorubicin, and Cyclophosphamide in the Treatment of Uterine Papillary Serous Carcinoma (UPSC)

Thirty patients with uterine papillary serous carcinoma were treated with intravenous cisplatin, doxorubicin, and cyclophosphamide (CAP) chemotherapy, a combination with proven efficacy against ovarian carcinoma. Nineteen patients were given CAP as an adjuvant soon after surgery. Eleven patients were treated after recurrence or failure of other first-line therapy. Of the patients treated adjuvantly, 11 (58%) were alive without evidence of disease with a median follow-up of 24 months. Eight patients (42%), all with metastatic disease at diagnosis, were dead of disease (DOD) with a median survival of 14 months. In the salvage group, all patients were DOD with a median survival of 21 months from diagnosis and a median survival from initiation of CAP of 7 months. Toxicity was observed in all patients, and there was one treatment-related death from cardiotoxicity. In the salvage group there were two partial responses and one complete response (response RATE = 27%). We conclude that intravenous CAP was ineffective in the treatment of metastatic or recurrent uterine papillary serous carcinoma, but deserves study as an adjuvant in patients without metastatic or with only microscopic extrauterine disease.     

Chemotherapy in Advanced Ovarian Carcinoma: Current Standards of Care Based on Randomized Trials

The mainstay of the treatment of advanced (stage III or IV) ovarian carcinoma is systemic therapy. The following review bases conclusions regarding standards of care on large, randomized trials of chemotherapy in advanced ovarian carcinoma. As of 1976, "standard" chemotherapy was single alkylating agent usually with melphalan. Studies of combination chemotherapy failed to show superiority over single alkylating agent until the introduction of cisplatin. The Gynecologic Oncology Group conducted a series of two trials in patients with large-volume disease, the first randomizing patients to either single-agent melphalan or a combination of doxorubicin and cyclophosphamide and the second to doxorubicin plus cyclophosphamide with or without cisplatin. These studies demonstrated superiority for the cisplatin-based combination in terms of overall response rate, clinical complete response rate, progression-free survival, and overall survival. Subsequent randomized trials demonstrated several important facts. First, platinum-based combinations yielded results superior to single-agent cisplatin. Second, a two-drug combination of cisplatin plus cyclophosphamide provides benefit equivalent to the three-drug combination of the same two drugs plus doxorubicin. Third, substitution of carboplatin for cisplatin yields similar results. Finally, dose escalation of chemotherapy by a factor of 2 does not offer a therapeutic advantage. The next major advance after the introduction of the platinum compounds was the demonstration of the activity of taxol, a new agent with a unique mechanism of action and apparent clinical non-cross-resistance with the platinum compounds. A recently completed GOG trial of cisplatin plus cyclophosphamide versus cisplatin plus taxol in patients with large-volume disease shows that the taxol-based combination has a superior overall response rate, clinical complete response rate, rate of achieving a state of no gross residual disease at second-look laparotomy, and progression-free survival. Survival analysis awaits maturation of the data, but the control arm has already been shown to have a median survival of 23.2 months with the median not yet reached for the taxol-based arm. These data suggest that a combination of taxol plus cisplatin should be considered the standard of care for patients with advanced ovarian carcinoma. Ongoing trials seek to define further the role of taxol in frontline chemotherapy for ovarian carcinoma. In conclusion, the standard chemotherapy for advanced ovarian carcinoma should be considered a combination of taxol plus a platinum compound.     

Treatment of advanced uterine sarcoma with vincristine,actinomycin D,and cyclophosphamide

Between 1971 and 1979, seventy-four patients with metastatic or advanced recurrent sarcoma of uterine origin were treated with combination chemotherapy consisting of vincristine, actinomycin D, and cyclophosphamide (Cytoxan). The probability of survival at 2 and 5 years was 23 and 15%, respectively. The response rate for patients with measurable disease was 28.9% (15.6% partial responses and 13.3% complete responses). The median duration of a complete response was 16 months and that of a partial response was 5.5 months. The median survival of the complete responders was prolonged when compared to nonresponders.     

Dual sequential non-cross-resistant chemotherapy for advanced stage squamous cell carcinoma of the cervix.

Forty-three patients with recurrent and metastatic squamous cell carcinoma of the cervix received a program of sequential combination chemotherapy incorporating induction with cisplatin, vinblastine, and bleomycin (PVB) and subsequent consolidation with 5-fluorouracil, doxorubicin, cyclophosphamide, and vincristine (FACV). The overall response rate was 62% and 10 patients (23%) achieved complete remission. Response status was improved in 11 patients at the completion of FACV after initial PVB therapy, including 9 complete remissions. The median survival for all patients in the study was 38 weeks and 50 weeks for the responding patients. Myelosuppression was the principal toxicity encountered and 10 episodes of neutropenic sepsis occurred, including one septic death. However, the only cumulative toxicity was peripheral neuropathy, although this was only moderate to severe in 2 patients. These results are encouraging, but will require confirmation in randomized comparison to cisplatin, presently accepted as standard single-agent therapy.     

Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study

OBJECTIVES: To estimate the objective response rate and toxicity associated with alternating megestrol acetate (MA) and tamoxifen citrate (T) in women with endometrial carcinoma. METHODS: Consenting patients with measurable recurrent or advanced endometrial carcinoma were eligible if they had not received prior cytotoxic or hormonal treatment. MA 80 mg BID x 3 weeks alternating with T 20 mg BID x 3 weeks orally was given. RESULTS: Of 61 patients entered, 56 eligible patients were evaluable for toxicity and response. Fifteen patients responded (12 complete, 3 partial) for an overall response rate of 27% (90% Confidence Interval: 17-38%). In 8 of 15 (53%) responders, response duration exceeded 20 months. The response rate was 38% in patients with histologic grade 1 tumors (n = 16), 24% in those with grade 2 disease (n = 17), and 22% among patients with grade 3 disease (n = 23). Women less than or equal to 60 years (n = 16) appear to have a better response rate than those >60 years (n = 40), 44% versus 20%. The response rate in patients with extra pelvic disease (n = 42) was 31% as compared to 14% in those with strictly pelvic and/or vaginal disease (n = 14). The median progression-free survival (PFS) was 2.7 months and median overall survival was 14.0 months. Two patients experienced a grade 4 thromboembolic event. Additional toxicities included one of each grade 3 gastrointestinal, grade 3 neurologic, and grade 3 genitourinary. CONCLUSION: A regimen of alternating megestrol acetate and tamoxifen is active in treating endometrial cancer and may result in a prolonged complete response (CR) in some patients.     

Cis-platinum, doxorubicin, and methotrexate treatment for recurrent cervical cancer

A combination of cis-platinum, doxorubicin (Adriamycin), and methotrexate was used to treat 28 patients with recurrent cervical cancer. Seven patients achieved a partial response with a median duration of ten months. Two patients achieved a complete response with a median duration of 14 months. The overall response rate was 32%. Ten patients with stable disease had a median progression-free interval of 4.5 months. Toxicity was acceptable.     

Malignant mixed mesodermal tumors of the uterus and ovary treated with cisplatin-based combination chemotherapy

Twelve patients with malignant mixed mullerian tumors were treated with combination chemotherapy at Vanderbilt University Hospital from 1977 through 1981. Nine patients, all of whom received combination chemotherapy with hexamethylmelamine, cyclophosphamide, doxorubicin, and cisplatin (HCAP), were evaluable for response. Objective responses (all partial responses) were noted in 3 (33.3%) (response rate greater than 10% and less than 55% with 90% confidence limits), a minimal response was noted in one patient, and stable disease in four (50%) patients. Responders survived longer (calculated from the initiation of HCAP) than nonresponders (median 112 vs 19 weeks). These results are not at present statistically different from previous studies utilizing doxorubicin alone, cisplatin alone, the combination of doxorubicin and DTIC, or the combination of vincristine, actinomycin D, and cyclophosphamide.     

Doxorubicin-cisplatin-vinblastine combination chemotherapy of advanced endometrial carcinoma: a Southwest Oncology Group Study

A combination of doxorubicin (30 mg/m2 iv), cisplatin (50 mg/m2 iv), and vinblastine (5 mg/m2 iv) repeated every 3-4 weeks was used to treat 55 patients with advanced stage III or IV or recurrent disease. Of the 42 fully evaluable patients, there were 3 complete responders (7%) and 10 partial responders (24%). Responses were of short duration (median of 8 months, range 3-15 months) and the median survival of all evaluable patients was only 10 months from the start of therapy. Leukopenia was the major toxicity and was at least moderate in two-thirds of patients. We conclude that the addition of cisplatin and vinblastine to doxorubicin does not improve the clinical utility of doxorubicin in patients with advanced endometrial cancer.     

Randomised trial comparing combinations of cyclophosphamide and cisplatin without or with doxorubicin or 4'-epi-doxorubicin in the treatment of advanced ovarian cancer

Forty-eight patients with FIGO stage III and IV epithelial carcinomas of the ovary were entered in this randomised trial. Radical surgery was performed and no residual tumor with a diameter greater than 2 cm was left behind. Of these patients 62.5% (10/16) had a complete or partial response on cyclophosphamide + cisplatin (CP) 87.5% (14/16) on cyclophosphamide + doxorubicin + cisplatin (CAP) and cyclophosphamide + 4'-epi-doxorubicin + cisplatin (CEP). The median time to progression was 3.5 months on CP, 12.5 months on CAP and 11.0 months on CEP. Patients treated with CAP combination chemotherapy had generally longer progression-free survival (log rank chi 2 = 5.4; P = 0.04). No significant difference was found, however, between patients on CAP and CEP. The median survival times were 12.5 months on CP, 26.5 months on CAP and 14.0 months on CEP. Patients treated with CAP combination chemotherapy had generally longer survival (logrank chi 2 = 9.08; P = 0.0099). No significant difference was found, however, between patients on CAP and CEP in terms of survival. Asymptomatic mild-to-moderate laboratory test toxicity occurred in 6-12% of patients on CP, 6-12% on CAP and no toxicity of this type and grade on CEP. Nausea and vomiting were also less severe and less frequent in the CEP group. Cardiotoxicity was seen in 12.5% (2/16) only in the CAP group.     

Advanced and recurrent carcinoma of the ovary treated with a combination of cyclophosphamide,doxorubicin, and cytosine arabinoside

Twenty-six patients with advanced or recurrent epithelial ovarian carcinoma, FIGO Stages III and IV, were treated with combination chemotherapy using cyclophosphamide, doxorubicin, and cytosine arabinoside (CARA). In 17 cases, CARA was initiated following failure to single-agent chemotherapy, in all cases, melphalan. Nine patients with advanced cancer received CARA as their primary chemotherapy after maximum cytoreductive surgery. The overall response rate was 27%; however, in patients without prior chemotherapy the response rate was 44%. There were 6 complete responders, 1 partial responder, 13 patients with stable disease, and 6 who failed to respond to therapy. Four of six complete responders had remission durations greater than 10 months. The median progression free interval (PFI) of patients with residual tumor diameters less than 2 cm was significantly longer (P ? 0.04) than the PFI of patients with greater initial tumor burden. The median PFI of complete responders was significantly longer (P = 0.007) than PFI of patients with less than complete response. Previously untreated patients had longer median PFI than those who had failed previous chemotherapy (P = 0.07). The major dose-limiting toxicity of CARA was thrombocytopenia. Other myelosuppression was moderate and no cardiotoxicity was encountered.     

Treatment of Advanced or Recurrent Endometrial Carcinoma with Single-Agent Carboplatin

Cisplatin and the combination of cisplatin, doxorubicin, and cyclophosphamide have documented activity in women with advanced or recurrent endometrial adenocarcinoma. However, response duration has been short and toxicity is substantial. To determine if similar activity could be obtained with less morbidity, we prospectively treated 33 patients with 360 mg/m² carboplatin given intravenously every 28 days. Mean patient age was 69 years (range 40-86); all had a Zubrod functional status of 2 or less. Seventeen patients had advanced primary tumors, and 16 had recurrent disease. Prior treatment included surgical resection in 29 cases, hormonal agents in 7, and radiotherapy in 22. No patient had received prior chemotherapy. Mean treatment was 5.7 cycles. Nine of 27 patients (33%) with measurable disease had objective responses, including three complete and six partial responses. Nonresponders included 10 patients with stable disease and 8 whose disease progressed while on treatment. Median time to response was 3 months. Median progression-free survival for responders and nonresponders was 5 and 4 months, respectively. At analysis, 20 patients had died of disease, 7 were alive with disease, and 6 were clinically free of disease. Disease-free patients include 1 with a complete response and 5 who began treatment without measurable disease. Median follow-up for surviving patients was 18 months (range 4-32). Treatment toxic effects were minimal and largely limited to myelosuppression; 3 patients had grade 3 thrombocytopenia, 1 had grade 3 neutropenia, and 5 had grade 3 anemia. Carboplatin has definite activity in endometrial carcinoma and offers a well-tolerated palliative therapeutic alternative.     

A short and intensive single-agent cisplatin regimen for recurrent carcinoma of the uterine cervix

Between May 1991 and September 1993, 36 patients with recurrent carcinoma of the uterine cervix were treated with single-agent cisplatin using an intensive regimen of four weekly cycles of 50 mg m⁻² followed in responders by a further four cycles given every fortnight. The response rate was 47% (95% CI: 27–66%), 56% in those with pelvic recurrence, and 38% in those with metastatic disease. All responses but one were seen within 4 weeks of commencing treatment. Three patients (9%) had a complete response, although in two cases this was of short duration. The treatment was moderately well tolerated and the principle toxicities were myelotoxicity and emesis. The median survival was 32 weeks, and the 18-month survival was 13%.
This regimen gives a response rate similar to that seen with more toxic combination chemotherapy regimens such as BIP (bleomycin, ifosfamide and cisplatin). It has the particular advantages of a short duration of treatment and early response, allowing treatment to be stopped after 4 weeks in non-responders. The response rate in pelvic recurrence was better than that seen in most previous chemotherapy trials, particularly as 78% of the evaluable patients with pelvic recurrence had previously received radical radiotherapy to the pelvis.
Weekly, followed by fortnightly cisplatin, is an appropriate palliative treatment for patients with recurrent carcinoma of the uterine cervix for whom chemotherapy is indicated.